Engineering liquid metal-based nanozyme for enhancing microwave dynamic therapy in breast cancer PDX model.

BACKGROUNDS: The novel concept of microwave dynamic therapy (MDT) solves the problem of incomplete tumor eradication caused by non-selective heating and uneven temperature distribution of microwave thermal therapy (MWTT) in clinic, but the poor delivery of microwave sensitizer and the obstacle of tumor hypoxic microenvironment limit the effectiveness of MDT. RESULTS: Herein, we engineer a liquid metal-based nanozyme LM@ZIF@HA (LZH) with eutectic Gallium Indium (EGaIn) as the core, which is coated with CoNi-bimetallic zeolite imidazole framework (ZIF) and hyaluronic acid (HA). The flexibility of the liquid metal and the targeting of HA enable the nanozyme to be effectively endocytosed by tumor cells, solving the problem of poor delivery of microwave sensitizers. Due to the catalase-like activity, the nanozyme catalyze excess H2O2 in the tumor microenvironment to generate O2, alleviating the restriction of the tumor hypoxic microenvironment and promoting the production of ROS under microwave irradiation. In vitro cell experiments, the nanozyme has remarkable targeting effect, oxygen production capacity, and microwave dynamic effect, which effectively solves the defects of MDT. In the constructed patient-derived xenograft (PDX) model, the nanozyme achieves excellent MDT effect, despite the heterogeneity and complexity of the tumor model that is similar to the histological and pathological features of the patient. The tumor volume in the LZH + MW group is only about 1/20 of that in the control group, and the tumor inhibition rate is as high as 95%. CONCLUSION: The synthesized nanozyme effectively solves the defects of MDT, improves the targeted delivery of microwave sensitizers while regulating the hypoxic microenvironment of tumors, and achieves excellent MDT effect in the constructed PDX model, providing a new strategy for clinical cancer treatment.

Metal ions and nanometallic materials in antitumor immunity: Function, application, and perspective.

The slightest change in the extra/intracellular concentration of metal ions results in amplified effects by signaling cascades that regulate both cell fate within the tumor microenvironment and immune status, which influences the network of antitumor immunity through various pathways. Based on the fact that metal ions influence the fate of cancer cells and participate in both innate and adaptive immunity, they are widely applied in antitumor therapy as immune modulators. Moreover, nanomedicine possesses the advantage of precise delivery and responsive release, which can perfectly remedy the drawbacks of metal ions, such as low target selectivity and systematic toxicity, thus providing an ideal platform for metal ion application in cancer treatment. Emerging evidence has shown that immunotherapy applied with nanometallic materials may significantly enhance therapeutic efficacy. Here, we focus on the physiopathology of metal ions in tumorigenesis and discuss several breakthroughs regarding the use of nanometallic materials in antitumor immunotherapeutics. These findings demonstrate the prominence of metal ion-based nanomedicine in cancer therapy and prophylaxis, providing many new ideas for basic immunity research and clinical application. Consequently, we provide innovative insights into the comprehensive understanding of the application of metal ions combined with nanomedicine in cancer immunotherapy in the past few years.

New anti-cancer explorations based on metal ions.

Due to the urgent demand for more anti-cancer methods, the new applications of metal ions in cancer have attracted increasing attention. Especially the three kinds of the new mode of cell death, including ferroptosis, calcicoptosis, and cuproptosis, are of great concern. Meanwhile, many metal ions have been found to induce cell death through different approaches, such as interfering with osmotic pressure, triggering biocatalysis, activating immune pathways, and generating the prooxidant effect. Therefore, varieties of new strategies based on the above approaches have been studied and applied for anti-cancer applications. Moreover, many contrast agents based on metal ions have gradually become the core components of the bioimaging technologies, such as MRI, CT, and fluorescence imaging, which exhibit guiding significance for cancer diagnosis. Besides, the new nano-theranostic platforms based on metal ions have experimentally shown efficient response to endogenous and exogenous stimuli, which realizes simultaneous cancer therapy and diagnosis through a more controlled nano-system. However, most metal-based agents have still been in the early stages, and controlled clinical trials are necessary to confirm or not the current expectations. This article will focus on these new explorations based on metal ions, hoping to provide some theoretical support for more anti-cancer ideas.

Metal-induced delayed type hypersensitivity responses potentiate particle induced osteolysis in a sex and age dependent manner.

It is widely recognized that innate macrophage immune reactions to implant debris are central to the inflammatory responses that drive biologic implant failure over the long term. Less common, adaptive lymphocyte immune reactions to implant debris, such as delayed type hypersensitivity (DTH), can also affect implant performance. It is unknown which key patient factors, if any, mediate these adaptive immune responses that potentiate particle/macrophage mediated osteolysis. The objective of this investigation was to determine to what degree known adaptive immune responses to metal implant debris can affect particle-induced osteolysis (PIO); and if this pathomechanism is dependent on: 1) innate immune danger signaling, i.e., NLRP3 inflammasome activity, 2) sex, and/or 3) age. We used an established murine calvaria model of PIO using male and female wild-type C57BL/6 vs. Caspase-1 deficient mice as well as young (12-16 weeks old) vs. aged (18-24 months old) female and male C57BL/6 mice. After induction of metal-DTH, and Cobalt-alloy particle (ASTM F-75, 0.4um median diameter) calvaria challenge, bone resorption was assessed using quantitative micro-computed tomography (micro-CT) analysis and immune responses were assessed by measuring paw inflammation, lymphocyte transformation test (LTT) reactivity and adaptive immune cytokines IFN-gamma and IL-17 (ELISA). Younger aged C57BL/6 female mice exhibited the highest rate and severity of metal sensitivity lymphocyte responses that also translated into higher PIO compared to any other experimental group. The absence of inflammasome/caspase-1 activity significantly suppressed DTH metal-reactivity and osteolysis in both male and female Caspase-1 deficient mice. These murine model results indicate that young female mice are more predisposed to metal-DTH augmented inflammatory responses to wear debris, which is highly influenced by active NLRP3 inflammasome/caspase-1 danger signaling. If these results are clinically meaningful for orthopedic patients, then younger female individuals should be appropriately assessed and followed for DTH derived peri-implant complications.

Transition metals and metal complexes in autophagy and diseases.

Transition metals refer to the elements in the d and ds blocks of the periodic table. Since the success of cisplatin and auranofin, transition metal-based compounds have become a prospective source for drug development, particularly in cancer treatment. In recent years, extensive studies have shown that numerous transition metal-based compounds could modulate autophagy, promising a new therapeutic strategy for metal-related diseases and the design of metal-based agents. Copper, zinc, and manganese, which are common components in physiological pathways, play important roles in the progression of cancer, neurodegenerative diseases, and cardiovascular diseases. Furthermore, enrichment of copper, zinc, or manganese can regulate autophagy. Thus, we summarized the current advances in elucidating the mechanisms of some metals/metal-based compounds and their functions in autophagy regulation, which is conducive to explore the intricate roles of autophagy and exploit novel therapeutic drugs for human diseases.

Multienzymes activity of metals and metal oxide nanomaterials: applications from biotechnology to medicine and environmental engineering.

With the rapid advancement and progress of nanotechnology, nanomaterials with enzyme-like catalytic activity have fascinated the remarkable attention of researchers, due to their low cost, high operational stability, adjustable catalytic activity, and ease of recycling and reuse. Nanozymes can catalyze the same reactions as performed by enzymes in nature. In contrast the intrinsic shortcomings of natural enzymes such as high manufacturing cost, low operational stability, production complexity, harsh catalytic conditions and difficulties of recycling, did not limit their wide applications. The broad interest in enzymatic nanomaterial relies on their outstanding properties such as stability, high activity, and rigidity to harsh environments, long-term storage and easy preparation, which make them a convenient substitute instead of the native enzyme. These abilities make the nanozymes suitable for multiple applications in sensing and imaging, tissue engineering, environmental protection, satisfactory tumor diagnostic and therapeutic, because of distinguished properties compared with other artificial enzymes such as high biocompatibility, low toxicity, size dependent catalytic activities, large surface area for further bioconjugation or modification and also smart response to external stimuli. This review summarizes and highlights latest progress in applications of metal and metal oxide nanomaterials with enzyme/multienzyme mimicking activities. We cover the applications of sensing, cancer therapy, water treatment and anti-bacterial efficacy. We also put forward the current challenges and prospects in this research area, hoping to extension of this emerging field. In addition to therapeutic potential of nanozymes for disease prevention, their practical effects in diagnostics, to monitor the presence of SARS-CoV-2 and related biomarkers for future pandemics will be predicted.

Challenges in Bone Tissue Regeneration: Stem Cell Therapy, Biofunctionality and Antimicrobial Properties of Novel Materials and Its Evolution.

An aging population leads to increasing demand for sustained quality of life with the aid of novel implants. Patients expect fast healing and few complications after surgery. Increased biofunctionality and antimicrobial behavior of implants, in combination with supportive stem cell therapy, can meet these expectations. Recent research in the field of bone implants and the implementation of autologous mesenchymal stem cells in the treatment of bone defects is outlined and evaluated in this review. The article highlights several advantages, limitations and advances for metal-, ceramic- and polymer-based implants and discusses the future need for high-throughput screening systems used in the evaluation of novel developed materials and stem cell therapies. Automated cell culture systems, microarray assays or microfluidic devices are required to efficiently analyze the increasing number of new materials and stem cell-assisted therapies. Approaches described in the literature to improve biocompatibility, biofunctionality and stem cell differentiation efficiencies of implants range from the design of drug-laden nanoparticles to chemical modification and the selection of materials that mimic the natural tissue. Combining suitable implants with mesenchymal stem cell treatment promises to shorten healing time and increase treatment success. Most research studies focus on creating antibacterial materials or modifying implants with antibacterial coatings in order to address the increasing number of complications after surgeries that are mostly caused by bacterial infections. Moreover, treatment of multiresistant pathogens will pose even bigger challenges in hospitals in the future, according to the World Health Organization (WHO). These antibacterial materials will help to reduce infections after surgery and the number of antibiotic treatments that contribute to the emergence of new multiresistant pathogens, whilst the antibacterial implants will help reduce the amount of antibiotics used in clinical treatment.

Uncemented tantalum metal components versus cemented tibial components in total knee arthroplasty: 11- to 15-year outcomes of a single-blinded randomized controlled trial.

AIMS: Total knee arthroplasty is an established treatment for knee osteoarthritis with excellent long-term results, but there remains controversy about the role of uncemented prostheses. We present the long-term results of a randomized trial comparing an uncemented tantalum metal tibial component with a conventional cemented component of the same implant design. METHODS: Patients under the age of 70 years with symptomatic osteoarthritis of the knee were randomized to receive either an uncemented tantalum metal tibial monoblock component or a standard cemented modular component. The mean age at time of recruitment to the study was 63 years (50 to 70), 46 (51.1%) knees were in male patients, and the mean body mass index was 30.4 kg/m2 (21 to 36). The same cruciate retaining total knee system was used in both groups. All patients received an uncemented femoral component and no patients had their patella resurfaced. Patient outcomes were assessed preoperatively and postoperatively using the modified Oxford Knee Score, Knee Society Score, and 12-Item Short-Form Health Survey questionnaire (SF-12) score. Radiographs were analyzed using the American Knee Society Radiograph Evaluation score. Operative complications, reoperations, or revision surgery were recorded. A total of 90 knees were randomized and at last review 77 knees were assessed. In all, 11 patients had died and two were lost to follow-up. RESULTS: At final review all patients were between 11 and 15 years following surgery. In total, 41 of the knees were cemented and 36 uncemented. There were no revisions in the cemented group and one revision in the uncemented group for fracture. The uncemented group reported better outcomes with both statistically and clinically significant (p = 0.001) improvements in knee-specific Oxford and Knee Society scores compared with the cemented group. The global SF-12 scores demonstrated no statistical difference (p = 0.812). Uncemented knees had better radiological analysis compared with the cemented group (p < 0.001). CONCLUSION: Use of an uncemented trabecular metal tibial implant can afford better long-term clinical outcomes when compared to cemented tibial components of a matched design. However, both have excellent survivorship up to 15 years after implantation. Cite this article: Bone Joint J 2020;102-B(8):1025-1032.

Metallosis after knee replacement: a review.

INTRODUCTION: Although metallosis is a well-known complication after total hip arthroplasty, little is known about this phenomenon after total (TKA) or unicompartmental knee arthroplasty (UKA). The aim of the present work was to review the current knowledge about the reasons and the diagnostic as well as therapeutic management of metallosis after knee arthroplasty. MATERIALS AND METHODS: A literature search was performed through PubMed until April 2019. Search terms were "metallosis" in combination with "knee", "knee prosthesis", "knee arthroplasty" and "knee replacement", respectively. All publications were analyzed regarding publication year, level of evidence, number of knees/patients treated, type of prosthesis, metallosis cause, time period between primary implantation and metallosis emergence, laboratory examination, treatment, complications and follow up. RESULTS: A total of 38 studies reporting on a total of 97 knees were identified. 29 studies reported on metallosis after TKA, 8 after UKA, and one study after both procedures. The time period between the primary implantation and metallosis emergence ranged between 6 weeks and 26 years. The most common reason was the failure of a metal-backed patellar component in 40%, followed by implant/structural- and PE failure (wear/dislocation) in 27% and 18% of the cases, respectively. Complete blood cell count, serum chemistry, erythrocyte sedimentation rate or C-reactive protein serum values were not indicative to diagnose metallosis. The diagnosis was confirmed by histopathological analyses and macroscopic evaluation during surgery. Depending on the particular cause various surgical procedures have been performed. Complete prosthesis exchange was the most common one showing no complications in 89.4% of the cases. CONCLUSIONS: Metallosis after knee arthroplasty is a rare and perhaps underestimated or under published complication. A systematic diagnostic approach is necessary for the timely and correct diagnosis. A thorough debridement as well as a (sub)total synovectomy should be always performed. In cases with a damaged component, a partial/complete prosthesis exchange leads to the best results. Should a malalignment be the cause of the metallosis, then it should be corrected within the revision surgery.

p-Cymene metallo-derivatives: An overview on anticancer activity.

Metallo-drugs have gained a huge attention among scientific community in the couple years. These drugs types have become important compounds in cancer therapy, where, for instance, platinum complexes are being used against many tumors worldwide. Nonetheless, to p-cymene metallo-derivatives a promising anticancer potential has also been increasingly proposed. In this sense, the present review aims to provide an in-depth revision of p-cymene metallo-drugs possible mechanisms of anticancer action for upcoming pharmaceutical and biotechnological prospects. p-cymene metallo-derivatives have revealed very interesting anticancer activities in various test systems, including cancer cells, being thus worth of note to deepen knowledge through clinical trials on their upcoming use for cancer chemotherapy combination.

Metal complexes in medicine and pharmacy - the past and the present II.

Therapy of malignant tumors is among the oldest and at the same time the most promising application areas of therapeutic metal complexes. The second part of our survey on metallopharmaceuticals deals with historical development and current state of coordination compounds in cancer therapy. It starts with the most famous and most successful metallodrug - cisplatin. After a brief account of the discovery of the anticancer properties of this substance follows the discussion of its chemical properties, toxicity, clinical application and resistance. Hereafter, complexes of other metals along with innovative research directions are addressed. The aim of this brief survey is to provide basic overview of the area of metallopharmacy, aimed at specialists in pharmacy and chemistry as well as at the general educated public.

Liquid metal based theranostic nanoplatforms: Application in cancer therapy, imaging and biosensing.

Liquid metals in recent years have grabbed the attention of researchers due to their expanded applicability not only in the field of therapeutics but also in theranostic. Acknowledged as a nuclear medicine due to its radioactivity, Gallium finds its widespread application in disorders of bone, calcium metabolism, and cancer. The present article deals with the advancement of gallium based nanoplatforms for therapy, imaging, and biosensing of cancers. The article describes the gallium based nanoconjugates and furnishes one's understanding of various therapeutic approaches such as photothermal therapy, sonodynamic therapy, radiotherapy, and immunotherapy along with various imaging platforms and biosensing platforms. A brief section related to patents on gallium based nanoplatforms in cancer has been included along with various molecular docking and simulation studies done on gallium. The recent advancement with respect to drug delivery gives an insight into the future perspective of gallium based nanoplatforms in the field of cancer theranostic.

Biological Activity of New Cichoric Acid-Metal Complexes in Bacterial Strains, Yeast-Like Fungi, and Human Cell Cultures In Vitro.

Cichoric acid (CA) belongs to the group of polyphenols, which occurs in a variety of plant species and it is characterized by anticancer, antibacterial, and antiviral properties. Selected polyphenols have the ability to combine with metal ions to form chelate complexes that reveal greater biological activity than free compounds. In order to study possible antimicrobial and anticancer effect of CA and its complexes with copper(II)/zinc(II)/nickel(II)/cobalt(II) we decided to conduct cytotoxicity tests to estimate the most effective concentrations of tested compounds. The results of the presented study demonstrated, for the first time, that the treatment with newly synthesized CA-metal complexes has anticancer and antimicrobial effects, which were examined in seven different cell lines: MCF-7, MDA-MB-231, and ZR-75-1 breast cancer cell lines, A375 melanoma cell line, DLD-1 cell line, LN-229 cell line, FN cell line; five bacterial strains: Escherichia coli, Pseudomonas aeruginosa, Staphylococcus epidermidis, Proteus vulgaris, Lactobacillus rhamnosus, yeast Sacchcaromyces boulardii, and pathogenic yeast-like fungi Candida albicans. The presented study indicates that CA-metal complexes could be considered as a potential supplementary tool in anticancer therapy, however, because of their possible toxic activity on fibroblasts, they should be used with caution. Some of the tested complexes have also preservative properties and positive influence on normal non-pathogenic microorganisms, which was demonstrated in selected microbial strains, therefore they may serve as food preservatives of natural origin with cytoprotective properties.

Local Biological Reactions and Pseudotumor-Like Tissue Formation in relation to Metal Wear in a Murine In Vivo Model.

Metal wear debris and released ions (CoCrMo), which are widely generated in metal-on-metal bearings of hip implants, are also found in patients with metal-on-polyethylene bearings due to the mechanically assisted crevice corrosion of modular taper junctions, including head-neck and neck-stem taper interfaces. The resulting adverse reactions to metal debris and metal ions frequently lead to early arthroplasty revision surgery. National guidelines have since been published where the blood metal ion concentration of patients must consistently be monitored after joint replacement to prevent serious complications from developing after surgery. However, to date, the effect of metal particles and metal ions on local biological reactions is complex and still not understood in detail; the present study sought to elucidate the complex mechanism of metal wear-associated inflammation reactions. The knee joints in 4 groups each consisting of 10 female BALB/c mice received injections with cobalt chrome ions, cobalt chrome particles, and ultra-high-molecular-weight polyethylene (UHMWPE) particles or PBS (control). Seven days after injection, the synovial microcirculation and knee joint diameter were assessed via intravital fluorescence microscopy followed by histological evaluation of the synovial layer. Enlarged knee diameter, enhanced leukocyte to endothelial cell interactions, and an increase in functional capillary density within cobalt chrome particle-treated animals were significantly greater than those in the other treatment groups. Subsequently, pseudotumor-like tissue formations were observed only in the synovial tissue layer of the cobalt chrome particle-treated animals. Therefore, these findings strongly suggest that the cobalt chrome particles and not metal ions are the cause for in vivo postsurgery implantation inflammation.

Metal-based phosphorus dendrimers as novel nanotherapeutic strategies to tackle cancers: A concise overview.

Several metal-based phosphorus dendrimers were prepared. The first series developed by us was the Cu(II) series. In this series, the most potent is the third generation-Cu(II) showing original mechanism of action with activation of the pro-apoptotic Bax protein. To our knowledge, it is the first example of nanoparticles displaying Bax protein activation and then cell death through apoptosis process. Interestingly, this dendritic-Cu(II) complex showed synergistic effect with doxorubicin. Based on these interesting anti-proliferative activities, we developed Au(III)-conjugated phosphorus dendrimers. The most potent is the third generation-Au(III) dendrimer which represents also a new and promising first-in-class anti-proliferative agent against both solid and liquid tumor cell lines. Then, in order to analyze the influence of the metal moiety distribution of Cu(II) and Au(III) on the surface of dendrimers, mix Cu(II)-Au(III)-conjugated phosphorus dendrimers were also prepared and tested as anti-proliferative agents. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology.

Intelligent Metal-Phenolic Metallogels as Dressings for Infected Wounds.

In this study, we report a metallogel developed based on metal-phenolic coordination of natural low-cost polyphenolic molecule and metal ions. Gelation occurs by mixing tannic acid (TA) and group (IV) titanium ions (TiIV) to form TA-TiIV gel. The TA-TiIV gel exhibits good capability to incorporate diverse metal ions by in situ co-gelation. Herein, five antimicrobial metal ions, i.e. ferric (FeIII), copper (CuII), zinc (ZnII), cobalt (CoII) and nickel (NiII) ions, were employed to include in TA-TiIV gels for developing intelligent dressings for infected wounds. The chemical and coordinative structures of TA-TiIV metallogels were characterized by UV-Vis and Fourier-transform infrared (FT-IR) spectroscopies. Cytotoxicity of antimicrobial metallogels was explored by MTT assay with NIH 3T3 fibroblasts. The release of metal ions was evaluated by inductively coupled plasma mass spectrometry (ICP-MS), indicating the different releasing profiles upon the coordinative interactions of metal ions with TA. The formation and disassembly of metallogels are sensitive to the presence of acid and an oxidizer, H2O2, which are substances spontaneously generated in infected wounds due to the metabolic activity of bacteria and the intrinsic immune response. The CuII releasing rates of TA-TiIV-CuII metallogels at different pH values of 5.5, 7.4 and 8.5 have been studied. In addition, addition of H2O2 trigger fast release of CuII as a result of oxidation of galloyl groups in TA. Consequently, the antimicrobial potency of TA-TiIV-CuII metallogels can be simultaneously activated while the wounds are infected and healing. The antimicrobial property of metallogels against Gram-negative Escherichia coli, and Gram-positive Methicillin-Resistant Staphylococcus aureus (USA300) and Staphylococcus epidermidis has been investigated by agar diffusion test. In an animal model, the TA-TiIV-CuII metallogels were applied as dressings for infected wounds, indicating faster recovery in the wound area and extremely lower amount of bacteria around the wounds, compared to TA-TiIV gels and gauze. Accordingly, the intelligent nature derived metallogels is a promising and potential materials for medical applications.

Evaluation of the Effect of a Tracheal Stent on Radiation Dose Distribution via Micro-CT Imaging.

PURPOSE: To study the effect of a metal tracheal stent on radiation dose distribution. METHOD: A metal tube bracket is placed in a self-made foam tube sleeve, and micro-computed tomography scanning is performed directly. The foam sleeve containing the metal bracket is placed in a nonuniform phantom for a routine computed tomography scan. The stents in conventional computed tomography images are replaced by the stents in micro-computed tomography images. Subsequently, 2 sets of computed tomography images are obtained and then imported to a radiotherapy treatment planning system. A single photon beam at 0° is designed in a field size of 10 cm × 10 cm, a photon beam of 6 MV, and a monitor unit of 200 MU. Monte Carlo algorithm is used to calculate the dose distribution and obtain the dose curve of the central axis of the field. The dose is verified with thermoluminescence dose tablets. RESULTS: The micro-computed tomography images of the tracheal stent are clearer and less false-like than its conventional computed tomography images. The planned dose curves of the 2 groups are similar. In comparison with the images without any stents in place, the doses at the incident surface of the stent in the conventional computed tomography images and at the stent exit surface in the rear of the stent increase by 1.86% and 2.76%, respectively. In the micro-computed tomography images, the doses at the incident surface of the stent and at the exit surface behind the stent increase by 1.32% and 1.19%, respectively. Conventional computed tomography reveals a large deviation between the measured and calculated values. CONCLUSION: Tracheal stent based on micro-computed tomography imaging has a less effect on radiotherapy calculation than that based on conventional computed tomography imaging.

Metal-based antitumor compounds: beyond cisplatin.

Despite improvements in the 5-year survival rate to over 80% in cancers, such as Hodgkin lymphoma and testicular cancer, more aggressive tumors including pancreatic and brain cancer still have extremely low survival rates. The establishment of chemoresistance, responsible for the reduction in treatment efficiency and cancer relapse, is one possible explanation for this setback. Metal-based compounds, a class of anticancer drugs, are largely used in the treatment of cancer. Herein, we will review the use of metal-based small molecules in chemotherapy, focusing on recent studies, and we will discuss how new nonplatinum-based agents are prompting scientists to increase drug specificity to overcome chemoresistance in cancer cells.

Development of Natural Product-Conjugated Metal Complexes as Cancer Therapies.

Platinum-based drugs have revolutionized cancer care, but are unfortunately associated with various adverse effects. Meanwhile, natural product scaffolds exhibit multifarious bioactivities and serve as an attractive resource for cancer therapy development. Thus, the conjugation of natural product scaffolds to metal complexes becomes an attractive strategy to reduce the severe side effects arising from the use of metal bearing drugs. This review aims to highlight the recent examples of natural product-conjugated metal complexes as cancer therapies with enhanced selectivity and efficacy. We discuss the mechanisms and features of different conjugate complexes and present an outlook and perspective for the future of this field.

Metallic wear debris collected from patients induces apoptosis in rat primary osteoblasts via reactive oxygen species­mediated mitochondrial dysfunction and endoplasmic reticulum stress.

Although total hip arthroplasty is considered to be an effective surgical procedure for treating hip joint diseases, it is hindered by implant wear debris, which induces aseptic loosening. Various cell types are involved in this pathogenesis; however, the interactions between wear debris and osteoblasts, which serve a crucial role in bone formation, have not been clearly illustrated. In the present study, minor metallic wear particles were collected from the interfacial membrane around loosened implants of patients, and the biological effects of these particles on rat primary osteoblasts were then explored. The results demonstrated that metallic wear debris was able to induce the apoptosis of treated cells in a concentration­ and time­dependent manner. Furthermore, it was identified that reactive oxygen species (ROS) generation increased, the mitochondrial membrane potential collapsed, and the mitochondria­caspase­dependent and endoplasmic reticulum (ER) stress apoptotic pathways were activated following metallic wear debris application. In addition, apoptosis and associated pathways were inhibited by the use of N­acetyl­L­cysteine, an antioxidant that suppresses ROS production, indicating that the ROS generation triggered ER stress, mitochondrial dysfunction and downstream cascades that contributed to cell apoptosis. These findings suggest that metallic wear debris­induced ROS serve an important role in the apoptosis of osteoblasts. This provides a valuable insight, not only into understanding the mechanisms underlying the involvement of osteoblasts in osteolysis, but also into a potential novel therapeutic approach to treat implant aseptic loosening.